The use of polymers as carriers for drugs, especially those drugs that have low water solubility at physiological pH, are toxic to the normal tissue, or cannot be administered in sufficient dosage, has gained interest in recent years [e.g., H. Ringsdorf, J. Polymer Sci.: Symp. 51, 135–153 (1975)]. A polymer carrier for antineoplastic drugs would provide a useful system for administration of these drugs because of their solubility, toxic and higher dose at delivery characteristics. Several efforts to deliver doxorubicin are illustrative of this effort [e.g., R. Duncan et al., “Preclinical Toxicology of a Novel Polymeric Antitumor Agent: I-copolymer-doxorubicin (PK1)”, Hum. Exp. Toxiocol. 17(2), 93–104 (1998); P. A. Vassey et al., “Phase I Clinical and Pharmacokietic Study of PK1 [N-(2-Hydroxypropyl)methacrylamide Copolymer Doxorubicin]: First Member of a New Class of Chemotherapeutic Agents—Drug-Polymer Conjugates”, Clin. Cancer Res. 5, 83–94 (1999); L. W. Seymour et al., “N-(2-Hydroxypropyl)methacrylamide Copolymers Targeted to the Hepatocyte Galactose-receptor; Pharmacokinetics in DBA2 Mice”, Br. J. Cancer 63, 859–866 (1991);
The prospect of using dendritic polymers as caters or carriers for drug delivery has been previously proposed on account of the unique structure and characteristics of these polymer molecules [R. Esfand and D. A. Tomalia, “Poly(amidoamine) (PAMAM) Dendrimers: from Biorimicry to Drug Delivery and Biomedical Applications”, research focus, DDT 6(8), 427–436 (Apr. 8, 2001); U.S. Pat. Nos. 5,338,532 and 5,527,524]. More specifically, it has been proposed that the external surface functionality and interior morphological characteristics of dendritic polymer molecules appear to be very promising for developing new methods for controlling drug release and targeted drug delivery systems. However, relatively little work has been done in specific areas of drug delivery. In particular, the use of dendritic polymers as effective caters for specific anti-tumor agents has not heretofore been demonstrated.
Certain platinum containing compounds, particularly carboplatin (cis-diamine(1,1-cylobutanedicarboxylato)platinum (II)) and cisplatin (cis-diamminedichloroplatinum) have been used in the treatment of ovarian cancer, lung cancer, testicular cancer, breast cancer, stomach cancer and lymphoma. However, because of the non-specific toxicity and poor water solubility of these platinum-containing compounds, the use of carboplatin and cisplatin has been relatively limited.
In order to overcome the non-specific toxicity and water solubility problems associated with cisplatin and carboplatin, it has been proposed to use linear polymers as carriers for these drugs. However, the use of linear polymers as caters in drug delivery systems has several disadvantages. A major disadvantage with linear polymer drug carriers is that they are heterogenous, polydisperse compositions containing various different molecular weight polymer molecules with a limited number of functional groups and/or reactive sites. Because linear polymer compositions are not comprised of molecules having a precisely defined structure, it is more difficult to maintain uniform polymer properties, drug delivery properties, and therapeutic efficacy. As a result it is relatively difficult to obtain regulatory (e.g., FDA) approval of the linear polymer-drug composites. Another disadvantage with the use of linear polymers as drug-carriers is that the location, and hence the availability, of the drug is difficult to control. In particular, the drug must either be bound covalently or non-covalently in a random unpredictable manner and the linear polymer structure lacks well-defined cargo space for the drug. The tendency of the drug to become buried in the linear polymer leads to greater unpredictability on account of the non-uniform or heterogeneous properties of the linear polymer molecules, and results in reduced drug efficiency because a significant proportion of the drug molecules are not effectively presented to the cell being treated. In some cases the random coil structure of the linear polymers may even prevent successful drug attachment within the coil and lead to passive entrapment, leading to uncontrolled drug release (e.g., random diffuse system), i.e., lack of uniformity in the timing of the drug release.
Accordingly, it would be highly desirable to provide a precisely defined drug delivery system for cisplatin and carboplatin, as well as related antineoplastic agents, which exhibit high drug efficiency, high drug carrying capacity, good water solubility, good stability on storage, reduced toxicity, and improved anti-tumor activity in vivo.
U.S. Pat. No. 5,338,532 teaches polymer conjugates comprising dense star polymers associated with a carried material, the disclosure of which is hereby incorporated by reference. [One type of dense star polymers is Starburst® polymers (trademark of The Dow Chemical Company) where the dendrimer is a polyamidoamine (PAMAM).] A variety of suitable applications for such conjugates are broadly discussed in U.S. Pat. No. 5,338,532, including the use of these conjugates as delivery vehicles for biologically active agents. However, the U.S. Pat. No. 5,338,532 does not specifically teach, claim, or even mention the use of polymer conjugates as delivery vehicles for antineoplastic agents, e.g., cisplatin, carboplatin, titanocene dichloride and diorganotin dihalides or other anitneoplactic agents. U.S. Pat. 5,338,532 only exemplifies the use of zero valence metals, and ionic or radioactive metals, specifically exemplifying Fe, Rh, Pd, Y, Fn, Pb, Gd, Mn and Gd.
In the interval between the filing of this continuation-in-part and the filing of U.S. Ser. No. 09/111,232, a journal article on the matter originally claimed, written by two of the present inventors, was published [see “Detidrimer-platinate: a Novel Approach to Cancer Chemotherapy”, Anti-Cancer Drugs, 10, 767–776 (1999)]. This article deals specifically with the formation of a dendrimer-cisplatin conjugate, i.e. a dendrimer-platinate. Although cisplatin is itself a platinum antineoplastic, the class as a whole is not taught by the article nor is it suggested that the methods of this article could be used or would be expected to work for the association of a dendrimer with other antineoplastic platinum-based analogues nor that the cisplatin is carried in the interior of the dendrimer.